1. Field of the Invention
The compounds of this invention are analogs of natural prostaglandins.
Natural prostaglandins are alicyclic compounds related to prostanoic acid, the structure of which is: ##STR2## By convention, the carbon atoms of I are numbered sequentially from the carboxylic carbon atom. An important stereochemical feature of I is the transorientation of the sidechains C.sub.1 -C.sub.7 and C.sub.13 -C.sub.20, an orientation common to all prostaglandins. In I, as elsewhere in this specification, solid lines (--) provide a reference plane (such as the cyclopentyl ring or the bonds among C.sub.1 -C.sub.7 and C.sub.13 -C.sub.20); a dashed line ( ) indicates projection of a covalent bond below such reference plane (alpha-configuration); while a wedged line ( ) represents direction above such plane (beta-configuration). These conventions apply to all structural formulae subsequently discussed in this specification. In some structures, however, a swung dash or serpentine line ( ) denotes orientation of a covalent bond either above or below the plane of reference (indicated by the Greek letter xi in the nomenclature of such structures).
Natural prostaglandins have the general structure, ##STR3## in which L and M may be ethylene or cis-vinylene radicals. Prostaglandins are characterized by the substituents on the cyclopentyl ring, the position of double bonds, if any, in the cyclopentyl ring and the number of double bonds in the side chains. When the cyclopentyl ring is fully saturated, carbonyl substituted at the 9-position and hydroxyl substituted at the 11-position an E-class prostaglandin is represented (PGE) and when there is a single double bond in the sidechains, i.e., L and M in Formula II are ethylene, a type-1 prostaglandin is represented. The naturally occurring E-class type 1 prostaglandin known as prostaglandin E.sub.1 or PGE.sub.1, is represented by the formula: ##STR4##
Formulae I, II and III depict the nat-isomer, i.e., the C.sub.7 -C.sub.8 bond in the alpha-configuration and the C.sub.12 -C.sub.13 bond in the beta-configuration. In the ent-isomer (which does not occur in nature), the direction of the bonds at C.sub.7 -C.sub.8 and C.sub.12 -C.sub.13 is reversed.
Recent research indicates that certain prostaglandins, including PGE.sub.1 and analogs thereof, elicit biochemical and physiological effects in a variety of mammalian systems. For example, in rats, PGE.sub.1 increases the release of growth hormone and in sheep it has been found to inhibit ovarian progesterone secretion. In mice, PGE.sub.1 has been found to increase thyroid activity whereas in hypophysectomized rats it has been found to stimulate stereordogensis in the adrenal glands.
In the mammalian male reproductive system, PGE.sub.1 contracts the smooth muscle of the vas deferens and in the female reproductive system PGE compounds contact uterine smooth muscle. Prostaglandins stimulate contraction of gastrointestinal smooth muscle in vivo and in vitro. In dogs, PGE.sub.1 inhibits gastric secretion. In most mammalian respiratory tracts, PGE compounds affect in vitro preparation of tracheal smooth muscle. The human lung normally contains PGE compounds; consequently, some cases of bronchial asthma may involve an imbalance in the production or metabolism of these compounds.
In addition, prostaglandins are involved in certain hematic mechanisms in mammals. For example, PGE.sub.1 inhibits aggregation of blood platelets in vitro. In a variety of mammalian cardiovascular systems, PGE compounds are vasodilators by virtue of their action on vascular smooth muscle.
Accordingly, it can be seen that prostaglandins and their analogs have broad clinical implications and research in this area continues in laboratories throughout the world.
2. Prior Art
U.S. Pat. No. 4,132,738 issued Jan. 2, 1979 discloses 15-deoxy-16-hydroxyprostaglandins of the structural formula: ##STR5## wherein J is R or S hydroxymethylene; R.sub.1 is hydrogen; R.sub.2 is hydrogen or together with R.sub.4 is a methylene chain of 2 to 3 carbon atoms such that a cycloalkyl of 5 to 6 carbon atoms is formed; R.sub.3 is hydrogen or methyl or together with R.sub.4 is a methylene or a lower alkylated methylene chain of 2 to 5 carbon atoms such that a cycloalkyl or lower alkylated cycloalkyl of 4 to 7 carbon atoms is formed or together with R.sub.4 forms a bicycloalkyl or bicycloalkenyl moiety. This patent also discloses PGE.sub.1 ester analogs of compounds of the above formula limited to structures wherein two of R.sub.2, R.sub.3, R.sub.4 and R.sub.5 form a cycloalkyl, lower alkylated cycloalkyl, bicycloalkyl or bicycloalkenyl. These prostaglandin analogs selectively produce bronchodilation and decrease gastric secretion in vivo.
U.S. Pat. No. 3,965,143 issued June 22, 1976 is directed to 16-hydroxy prostaglandin analogs which are acids and esters represented by the structural formula: ##STR6## where R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.6 and R.sub.7 can be hydrogen or a lower alkyl radical and R.sub.8 is an alkyl group containing 5 to 7 carbon atoms. In addition, this patent states that x can be carbonyl, V can be hydroxymethylene, Y can be ethylene and Z can be trans vinylene.
Netherlands Patent Application No. 73-10776, U.S. Application Ser. No. 274,769, discloses acids and esters of 16-hydroxy prostaglandin analogs represented by the structural formula: ##STR7## In the above formula R.sub.1 can be hydroxy, Y can be carbonyl, Z can be polymethylene of 3 to 8 carbon atoms, R.sub.3 can be hydroxy or an alkoxy group having from 1 to 12 carbon atoms and R.sub.2 can be --CH.dbd.CH--CH.sub.2 --R" where R" can be a straight chain alkyl group having from 2 to 10 carbon atoms and substituted with a hydroxy or triphenylmethoxy group or a straight chain alkyl group having from 2 to 6 carbon atoms and having one branched alkyl group of from 1 to 3 carbon atoms and substituted with a hydroxy or triphenylmethoxy group.